Primary leiomyosarcoma of the spine: an analysis of imaging manifestations and clinicopathological findings

Background Primary leiomyosarcoma of the spine is extremely rare and lacks specific clinical symptoms. This study investigated the imaging manifestations and clinicopathological findings of primary leiomyosarcoma of the spine, aiming to improve the radiologists’ understanding of the disease and reduce misdiagnoses. Methods The clinical, imaging, and pathological manifestations in eleven patients with pathologically confirmed primary leiomyosarcoma of the spine were retrospectively analyzed. The imaging features analyzed included lesion location, shape, border, size, and density/intensity, and adjacent bone destruction status, residual bone trabeculae, vertebral compression, and contrast enhancement. Results The patients’ primary clinical symptom was usually focal pain. Primary leiomyosarcoma of the spine was mostly a solitary lesion and tended to occur in the posterior elements. The tumors had a lobulated shape with osteolytic bone destruction, ill-defined borders, and could involve multiple segments. Computed tomography (CT) examination showed isodense masses. Six patients showed residual bone trabeculae. Two patients had miscellany T2-weighted imaging (T2WI) signals, while the tumor and spinal cord of the remaining patients were isointense on T1-weighted imaging (T1WI) and T2WI. Among the seven patients who underwent contrast-enhanced scanning, six displayed homogeneous enhancement. Eight patients underwent gross-total tumor resection with no recurrence. Conclusions Primary leiomyosarcoma of the spine tends to be a solitary lesion in the posterior elements and appears as a lobulated mass with osteolytic bone destruction and an ill-defined border. The tumor and spinal cord can be isointense on T1WI and T2WI. Contrast-enhanced scanning displays homogeneous enhancement. The lesion tends not to recur after surgical gross-total tumor resection.


Background
Leiomyosarcoma is a rare malignant spindle cell neoplasm that develops in smooth muscles and accounts for nearly 7% of the soft tissue sarcomas [1,2]. It usually occurs in the retroperitoneum and peritoneal cavity, in organs such as the gastrointestinal tract and the uterus. Leiomyosarcoma in the bones is rare, accounting for 0.06% of the primary and 0.14% of the malignant bone tumors [3]. Primary leiomyosarcomas in the spine are extremely rare, with only a dozen cases reported in the literature [4]. To the best of our knowledge, no series of imaging manifestations of primary leiomyosarcoma of the spine is available in the literature. This study reviewed the clinical features, imaging manifestations, and pathological findings of eleven cases of pathologically confirmed primary leiomyosarcoma of the spine, diagnosed over the past sixteen years, to improve the understanding of the disease and reduce misdiagnoses.

Patients
The Institutional Review Board of our hospital approved this retrospective study, and the requirement for informed consent was waived. This study retrospectively reviewed the clinical features, imaging manifestations, and pathological findings of eleven cases of pathologically confirmed primary leiomyosarcoma of the spines between January 2006 and May 2022. Of the eleven patients, five were male, and six were female. All patients underwent computed tomography (CT) examination, which included contrast-enhanced CT examination in three. Ten patients underwent magnetic resonance imaging (MRI), which included contrast-enhanced MRI examination in six. All lesions were surgically resected or subjected to CT-guided biopsy, and the diagnosis was confirmed by pathology.

Imaging examination
CT examination was made using a Siemens Somatom Definition Flash dual-source scanner (Siemens, Erlangen, Germany) or GE Discovery CT 64 VCT (GE Medical System, Chalfont St. Giles, UK). The parameters were: tube potential, 120 kV; tube current, 163-300 mAs; thread pitch, 0.980; slice thickness, 3 mm; slice spacing, 3 mm. The sagittal and coronal views were reconstructed. For enhanced scanning, a non-ionic contrast agent (Iopamiro; 350 mg I/mL) was injected via the elbow vein, using a high-pressure injection system at a dose of 2 mL/kg and a rate of 3 mL/s. MRI scanning was performed using a GE Discovery MR750 3.0 T scanner (GE Healthcare, Piscataway, NJ, USA) or a Siemens Magnetom Trio Tim 3.0 T scanner (Siemens, Erlangen, Germany). Standard T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) scans were acquired with a surface coil, slice thickness of 3.0 mm, and slice spacing of 3.3 mm. The sequence scanning parameters were: T1WI: repetition time (TR), 400-800 ms and echo time (TE), 10-30 ms; T2WI: TR, 2500-4000 ms and TE, 50-120 ms. Scanning sequences included T1WI and axial, sagittal, coronal, and fatsuppressed T2WI. Gadolinium (Gadopentetate dimeglumine; Beilu Pharmaceutical, Beijing, China) was used as the contrast enhancement agent at 0.2 mL/ kg, injected via an elbow vein under high pressure at a rate of 1.0 mL/s. Fat-suppressed T1WI was performed after injection with the following parameters: TR, 571-652 ms; TE, 9.8-11.2 ms.

Image analysis
Two radiologists experienced in spinal tumor diagnosis (X.Y.X. with ten years of experience and J.H.Z. with five years of experience) independently analyzed the CT and MRI images. Details noted included the lesion location, shape, border, mass size, and density/intensity, and the adjacent bone destruction status, vertebral compression, nerve root compression, spinal cord compression, and degree of contrast enhancement. Inconsistencies were resolved by discussion and consultation.

Pathological examination
All lesions were surgically resected or subjected to CTguided biopsy. For CT-guided biopsy, the patients were placed in a lateral or prone position, the region was sterilized and anesthetized layer-by-layer with 1% lidocaine. A coaxial biopsy needle was used as the trocar. An automatic biopsy needle was used to obtain the specimens, which were fixed in 10% formalin. Following biopsy, the patients were rescanned to rule out any complications. Pathological examinations included routine hematoxylin and eosin (HE) and immunohistochemical staining. The markers used included smooth muscle actin (SMA), vimentin, epithelial membrane antigen (EMA), S-100, and CD34.

Clinical features
The median patient age was 55 (range 17-77) years. One patient had multiple lesions. The lesion locations of the Keywords: Spine, Magnetic resonance imaging, Computed tomography remaining ten patients were as follows: cervical vertebrae in three; thoracic vertebrae in five; lumbar vertebrae in one; thoracolumbar region in one. The main clinical manifestations were pain, weakness, numbness, and movement restriction. Among the eleven patients, one underwent radiotherapy, two underwent subtotal resection, and the remaining eight underwent gross-total tumor resection with postoperative radiotherapy in five. Re-examinations were performed 3, 6, and 12 months post-operatively. Follow-up was performed once every 6-12 months if no recurrence was detected. The two patients who underwent subtotal resection showed disease progression at the 6-month follow-up examination. The patient who underwent radiotherapy showed no progression at the 3-month follow-up assessment. The eight patients treated by gross-total tumor resection had no recurrence. Non-recurrent patients were those with no tumor detected for at least one year. The patient information is presented in Table 1.

Imaging manifestations
The largest single-lesion tumor was in the T10-L1 segment. Vertebral body and/or posterior element involvement were limited to a single level in six patients and showed multi-level involvement in five. The lesions were centered in the posterior elements and extended into the vertebral body in eight patients, while the lesions were centered in the vertebral body and extended into the posterior elements in the remaining three. Masses that invaded the vertebrae or paravertebral tissues in nine patients displayed a lobulated shape. Osteolytic bone destruction was noted in eight patients, and expansive bone destruction in three. Nine of the eleven patients showed ill-defined borders, while the border of the remaining two was well defined. Six patients had residual bone trabeculae. The vertebrae of three lesions showed pathological compression fractures. All lesions had the same density as the surrounding muscles, with a mean radiodensity of 50 Hounsfield units (HU). MRI was isointense to the spinal cord signal in T1WI of ten patients and T2WI of eight. Two patients showed miscellany intensity on T2WI. Spinal cord compression was noted in four patients, and nerve root compression in seven. Among the seven patients who underwent contrast-enhanced scanning, six exhibited homogeneous enhancement. The details  Table 2 and Figs. 1, 2, 3 and 4.

Discussion
Leiomyosarcoma, first reported in 1965, is a rare sarcoma type, accounting for < 0.7% of all primary malignant bone tumors [5]. The etiology of primary leiomyosarcoma of the bone is unclear. The histological features of leiomyosarcoma of the bone are the same as those of leiomyosarcoma found in other tissues. Some studies suggested that the lesions might be derived from smooth muscle cells within the bone marrow cavity or mesenchymal stem cell that have not differentiated into smooth muscle cells [6][7][8]. Primary leiomyosarcoma rarely occurs in the bones. When it does, the epiphysis of the long bones in the lower limb, particularly near the knee joint, is the most common location [8]. Leiomyosarcoma in the spine is extremely rare, with the thoracic vertebrae being the most affected segment [4,9]. Leiomyosarcoma can occur at any age, but it is more common in middle-aged individuals. The incidence rates in males and females are roughly equal. Primary leiomyosarcoma of the spine lacks specific clinical symptoms. Patients usually present with focal pain that might be accompanied by weakness, numbness, movement restriction, or paresthesia of the extremities [2]. These manifestations depend primarily on the location and size of the lesion. Primary bone leiomyosarcoma might form soft tissue masses and cause pathological fractures [8]. When the tumor encroaches and presses the adjacent nerves or spinal cord, it could cause movement and sensory disturbances in the corresponding innervation area [10]. The patients in our study presented with typical symptoms such as focal pain, weakness, numbness, and movement restriction, with three patients presenting with pathological compression fractures, consistent with previous reports [4,8]. Standard radiography has limited diagnostic value, and imaging manifestations often lack specificity. CT and MRI examinations can clearly show changes in the bone and invasion of the surrounding soft tissue. CT is more valuable in detecting changes in the bone structure such as bone destruction and residual bone trabeculae than MRI. Previous studies have suggested that primary bone leiomyosarcoma lacks specific imaging manifestations [7,8,11]. We found in this study that some imaging features appeared frequently, providing some valuable information for diagnosis of primary leiomyosarcoma of the spine. Primary leiomyosarcoma of the spine usually presents as s solitary lesion, tends to occur in the posterior elements, and often has a lobulated shape with osteolytic bone destruction and ill-defined borders. Furthermore, a single lesion might involve multiple spinal segments. CT examination of our patients demonstrated that some had residual bone trabeculae and pathologic compression fractures. T1WI and T2WI scans of eight patients were isointense to the spinal cord, and contrast-enhanced scans displayed apparent homogeneous enhancement. We speculate that these findings are related to the dense arrangement and large nuclear-cytoplasmic ratio of the tumor cells.
The incidence of primary leiomyosarcoma of the spine is extremely low. In the absence of specific clinical symptoms, conclusive diagnosis needs pathological findings. Leiomyosarcoma pathology is divided into normal, epithelial-like, and polymorphic types [12]. The histopathological features of primary leiomyosarcoma of the bone depending on the histological grade [10]. Well-differentiated tumors consist of a few spindle-shaped cells arranged in bundles, with thin and granular cytoplasm and relatively dense fibrous components. The nuclei are round and blunt at both ends, with mild nuclear atypia and few independent intact cells. High-grade leiomyosarcoma cells are densely arranged, independent intact cells are common, diverse-sized and disordered spindle cells, and prominent nuclear atypia [10]. Microscopic examination shows elongated and spindle-shaped tumor cells, rich in cytoplasm, with many nuclear fissions. We have also observed giant cells with obscure necrosis. Routine HE staining often cannot distinguish between normal tissue and undifferentiated sarcoma, so immunohistochemical staining plays a very important role in diagnosing primary leiomyosarcoma of the spine. Immunohistochemical staining of spinal leiomyosarcomas showed positive expression of tumor cell SMA and vimentin, negative expression of CD34 and EMA, and focal weakly positive expression of the S-100 protein [13]. SMA is the most sensitive and relatively specific marker of bone leiomyosarcoma [14]. All eleven cases in this study showed pathological features typical to bone leiomyosarcoma.
Primary leiomyosarcoma of the spine must be distinguished from other spine tumors. First, bone metastasis of other leiomyosarcomas such as those of the gastrointestinal tract, uterus, kidney, and other soft tissues should be ruled out [2,9]. This possibility can be ruled out by checking the patient's cancer history and performing Table 2 Imaging manifestations of the 11 patients with primary leiomyosarcoma of the spine The patient number in Table 2 is consistent with that in Table 1 No Location  [4]. Second, primary leiomyosarcoma of the spine should be differentiated from plasmacytoma that often occurs in older adults. Both can be isointense to the spinal cord in T2WI with apparent homogeneous enhancement. However, beyond the background osteoporosis, bones with plasmacytomas are more prone to compression fracture, and the shape of soft tissue mass is irregular or almost round. Primary leiomyosarcoma of the spine should also be distinguished from giant-cell tumor of the bone (GCTB) as both have similar clinical symptoms. However, spinal GCTB often show miscellany intensity on MRI, and mostly affect the vertebral body rather than the posterior elements [15,16]. Primary leiomyosarcoma of the spine is a highly malignant tumor. Gross-total resection with microscopically negative margins is the leading treatment method [2,14,17], aiming to reduce postoperative recurrence rate. It is sometimes combined with contemporaneous or stagingdependent radical resection to relieve nerve compression and pain. Pedicle screw or anterior fixation is used to restore spinal stability. Radiotherapy and chemotherapy can help relieve the clinical symptoms. However, some scholars believe that primary leiomyosarcoma of bones is insensitive to these treatments, which cannot improve the surgical outcomes significantly [13,14,17]. Therefore, the effect of postoperative radiotherapy and chemotherapy on prolonging the patients' survival remains controversial. In our study, the eight patients who underwent gross-total tumor resection showed no recurrence, suggesting that primary leiomyosarcoma of the spine was not easy to recur after complete resection. Conversely, the two patients who underwent subtotal resection showed disease progression by the 6-month follow-up. One patient underwent radiotherapy alone; however, the effect of radiotherapy remains to be proven as the followup time in this case was short.
This study represents a preliminary summary of the imaging manifestations and clinicopathological findings of primary leiomyosarcoma of the spine. Although some valuable findings were obtained, the study had several limitations. First, the study was on very rare disease, vastly limiting the number of cases we could assess. Second, the data integrity cannot be guaranteed since the  imaging examinations of some patients were not comprehensive. In the future, we will expand the sample to validate and refine our results.

Conclusion
Primary leiomyosarcoma of the spine is extremely rare and lacks specific clinical symptoms. The imaging manifestations had certain specificity. These tumors were solitary lesions that tended to occur in the posterior elements and appear as lobulated masses with osteolytic bone destruction and ill-defined borders. Furthermore, singlelesion primary leiomyosarcoma of the spine can involve multiple segments. These tumors can be isointense to the spinal cord on T1WI and T2WI. Contrast-enhanced scanning displayed clear homogeneous enhancement. Radiologists should consider primary leiomyosarcoma of the spine when observing these imaging features. The final diagnosis requires confirmation by pathology and immunohistochemical staining. Recurrence rarely occurs after gross-total tumor resection. Author contributions JZ and YC contributed equally to the article. JZ and YC were major contributors in writing the manuscript. XX and QW participated in the data collection. KL and EZ were involved in tables and figure generating. NL contributed to the idea design of the paper and the modification of the final draft. All authors read and approved the final manuscript.

Funding
This study has received funding by National Natural Science Foundation of China (No. 81971578), Beijing Municipality Natural Science Foundation (NO. Z190020), and Clinical Key Project of Peking University Third Hospital (NO. BYSY2018007).

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations Ethics approval and consent to participate
This study was conducted following the Declaration of Helsinki. The Institutional Review Board of our hospital approved study protocol and all Fig. 4 A 30-year-old male with T7-T8 primary leiomyosarcoma. A Axial computed tomography (CT) showed an ill-defined isodense mass in the posterior elements of T7-T8; B Sagittal CT bone window showed bone destruction in the posterior elements of T7-T8; C T1 weighted imaging (T1WI) in sagittal view showed an isointense mass; D T2 weighted imaging (T2WI) in axial view showed a lobulated mass; E T2WI in sagittal view showed an isointense mass; F the diffuse spindle cell hyperplasia confirmed to be a feature of interstitial tumors. The tumor cells were visibly atypical, and the nuclear fission rate was high (HE, ×400)